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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
  • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
  • C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
  • C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
  • C07C33/025—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/203—Unsaturated compounds containing keto groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
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  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/12—Acetic acid esters
  • C07C69/14—Acetic acid esters of monohydroxylic compounds
  • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
  • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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  • C07C69/96—Esters of carbonic or haloformic acids
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

• This invention provides a novel synthesis for vitamin E which has the structure ##STR1## through the reaction in the presence of a palladium containing catalyst, of a compound of the formula: ##STR2## wherein R 4 is lower alkyl; and R 3 taken together with its attached oxygen atom forms an ether hydroxy protection group with a compound of the formula: ##STR3## wherein the dotted bond represents an unsaturated bond or an unsaturated bond which is hydrogenated; and R taken together with its attached oxygen atom forms an hydrolyzable ester hydroxy protecting group or through the reaction of a compound of the formula ##STR4## wherein R 3 is as above with a compound of the formula ##STR5## wherein the dotted bond is as above; followed by treatment with a palladium containing catalyst or through the catalyzed reaction of a compound of the formula ##STR6## wherein R 6 is aryl or lower alkyl and R 3 is as above with a compound of the formula III.
• lower alkyl includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms such as methyl and ethyl.
• lower alkoxy dneotes lower alkoxy groups containing 1 to 7 carbon atoms preferably 1 to 7 carbon atoms, such as methoxy, ethoxy, i-propoxy, t-butoxy, etc.
• lower alkanoic acid comprehends an alkanoic acid of from 1 to 7 carbon atoms such as formic acid and acetic acid.
• lower alkanoyl designates the monovalent radical formed from a lower alkanoic acid by removal of the OH group on the COOH moiety.
• preferred lower alkanoyl groups are acetyl, pivaloyl, butyryl, propionyl with acetyl being especially preferred.
• halogen of "halo”, unless otherwise stated, comprehends all halogens such as fluorine, chlorine, bromine and iodine.
• Alkali metal includes all alkali metals such as lithium, sodium and potassium.
• a thickened taper line ( ⁇ ) indicates a substituent which is in the beta-orientation (above the plane of the molecule)
• a wavy line ( ) indicates a substituent which is in either the alpha- or beta-orientation or mixtures of these isomers.
• aryl signifies mononuclear aromatic hydrocarbon groups such as phenyl, which can be unsubstituted or substituted in one or more positions with a lower akylenedioxy, nitro, halo, a lower alkyl or a lower alkoxy substituent, and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, etc., which can be unsubstituted or substituted with one or more of the aforementioned groups.
• the preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl.
• ether hydroxy protecting group designates any ether group for protecting a hydroxy group which, upon acid catalyzed cleavage or hydrogenolysis yields the free hydroxy group.
• Suitable ether protecting groups are, for example, the tetrahydropyranyl, benzyl, t-butyl or 4-methoxy-tetrahydropyranyl ethers.
• arylmethyl ethers such as benzhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl or tri(lower alkyl)silyl ethers such as trimethylsilyl ether diethyl-t-butylsilyl ether or dimethyl-tert-butylsilyl ether.
• Acid catalyzed cleavage is carried out by treatment with an organic or inorganic acid.
• the preferred inorganic acids are the mineral acids such as sulfuric acid, hydrohalic acid, etc.
• the preferred organic acids are lower alkanoic acids such as acetic acid, para-toluenesulfonic acid, etc.
• the acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium. Where an organic acid or alcohol is utilized, the organic acid or alcohol can be the solvent medium. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. In carrying out such cleavage, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure.
• hydrolyzable ester hydroxy protecting group denotes ester protecting groups where the hydroxy substituent is protected by esterification with an organic acid to form an ester which upon hydrolysis yields the free hydroxy substituent.
• preferred hydrolyzable esters which can be utilized to protect the hydroxy group are those esters formed by reacting the hydroxy group with a lower alkanoic acid containing from 1 to 7 carbon atoms present acetic acid, propionic acid, butyric acid, as well as aroic acids such as benzoic acid and carbonic acids of the formula ##STR9## wherein R 2 is lower alkyl as well as lower alkoxy-lower alkanoic acids where the lower alkoxy is as above and the lower alkanoic acids contain from 2 to 7 carbon atoms.
• the compound of formula V can be prepared from a compound of the formula: ##STR10## wherein the dotted bond is as above via the following intermediate ##STR11## wherein the dotted bond is as above.
• Compound of formula VIII is converted to the compound of formula IX by condensing the compound of formula VIII with acetone. Any of the conditions conventional in condensing aldehyde with acetone to produce an alpha, beta-unsaturated ketone can be utilized in carrying out this conversion.
• the compound of formula IX can be converted to the compound of formula V by treating the compound of formula IX with a reducing agent. Any conventional reducing agent, which will reduce a ketone to a hydroxy group can be utilized in carrying out this reaction.
• the conventional reducing agents are alkali metal aluminium hydrides, alkali metal borohydrides and aluminium isopropoxides. Any of the conditions conventionally utilized with respect to these reducing agents can be utilized in carrying out this reaction to produce the compound of formula V.
• the compound of formula VIII is utilized where the methyl substituent at the 3-position has an R configuration. Condensation with acetone as described above, produces the compound of formula IX where the methyl substituent in the 6 position has the R configuration.
• the compound of formula V thus produced has the methyl substituent at the 6 position in the same configuration as in the compound of formula IX.
• the compound of formula V can be converted by means of an enzymatic reaction into enantiomerically and diastereomerically pure compounds of formula III-A and V-A.
• the compound of formula V is first esterified with a suitable hydrolyzable ester hydroxy protecting group such as those mentioned hereinbefore, to produce the compound of formula III where the methyl substituent at the 2-position is RS and the methyl substituent at the 6 position is 6R.
• R is preferably a lower alkanoyl group most preferable butyryl.
• the esterification of the hydroxy group on the compound of formula V is carried out by conventional means, such as by reaction with a lower alkanolic acid, carbonic acid or reactive derivative thereof.
• the carbonate esters are formed in the usual manner by reacting the compound of formula V with a lower alkyl haloformate.
• the conditions conventional in preparing these lower alkanoyl ester and carbonate ester derivatives can be utilized in converting the compound of formula V into a suitable ester.
• the 2RS,6R mixture of diastereomers of formula III can be converted into a mixture of the 2R,6R stereoisomer of formula V-A and the 2S,6R diastereomer of formula III-C by enzymatic hydrolysis.
• the compound of formula III in its 2RS form is specifically hydrolysed to produce the 2R,6R compound of formula V-A.
• This enzymatic reaction can be utilized to convert a 2RS compound of formula III to the 2S compound of formula III while keeping the same configuration of the methyl substituent at the 6-position.
• the 2RS isomer of formula III dispersed in an aqueous medium is treated with an esterase enzyme.
• Any conventional esterase enzyme can be utilized to carry out this reaction.
• the esterase enzymes utilized in carrying out this reaction are lipases, particularly pancreatic lipases and lipases of bacterial and fungal origin.
• the choice of a particular catalytically effective amount of enzyme will depend upon factors within the control of one skilled in the art. These factors include the amount of starting material, the enzyme source, the unit activity of the enzyme, the purity of the enzyme and the like.
• excesses of a catalytically effective amount of the esterase enzyme can be utilized. However, no additional beneficial results are to be achieved through the use of large excesses of enzyme.
• the compound of formula III is suspended in an aqueous medium.
• emulsifying agents may be utilized to enhance the emulsification of the compound of formula III in the aqueous medium.
• emulsifying agents which can be utilized in accordance with this invention are included: sodium taurocholate, ammonium salts derived from fatty alcohols, and alkali metal salts of bile acids.
• the reaction medium can contain an inert organic solvent for the compound of formula III. Any conventional inert organic solvent which does not denature the enzyme can be utilized.
• the conventional solvents are included acetonitrile, dimethylsulfoxide, etc.
• the enzymatic hydrolysis is carried out at a pH from 6 to 8, preferably at a pH of from 7.4 to 7.6.
• Any conventional method of maintaining the pH of the reaction mixture at the aforementioned pH can be utilized. Among the preferred methods is by means of buffers or automatic titration.
• the enzymatic hydrolysis of the compound of formula III produces the compound of formula V-A in admixture with the compound of formula III-C.
• These compounds can be easily separated once the enzymatic hydrolysis is stopped, by removing through filtration the enzyme from the reaction medium. Any conventional method of separation can be utilized to isolate the compound of formula V-A from the compound of formula III-C. Among the conventional means for separating these two compounds are included extraction and distillation.
• the compound of formula III-A can be prepared by esterification as described hereinbefore from the compound of formula V-A produced through enzymatic hydrolysis.
• the compound of formula V-A can be converted to the compound of III-A by esterification such as described hereinbefore in connection with the conversion of the compound of formula V to the compound of formula III.
• the compounds of formula II of formula II-A can be reacted with the compounds of formula III or III-A to produce an intermediate in the synthesis of vitamin E or its optically active isomers.
• the compound of formula IV is formed from the compound of formula ##STR13## wherein R 3 is as above via the following intermediate ##STR14## wherein R 3 is as above and X is halogen.
• the compound of formula IV-A is desired, the compound of formula ##STR15## is utilized as the starting material rather than the compound of formula X.
• the stereoconfiguration of the compound of formula X or X-A is carried through the entire process of this invention.
• the compound of formula X or X-A is converted to the compound of formula X-B having the same stereoconfiguration as the compound of formula X or X-A by halogenation. Any conventional method of converting an organic acid to the corresponding acid halide can be utilized in this conversion.
• the compound of formula X-B is converted to the compound of formula IV by reacting the compound of formula X-B with Meldrum's acid according to conventional procedures such as disclosed by Oikawa, Sugano, et al., J. Org. Chem., 1978, 43 2087; and Davidson, and Bernhardt, J. Am. Chem. Soc., 1948, 70 3426. Through this reaction the compound of formula IV or the compound of formula IV-A is formed depending upon the stereo-configuration of the starting material, as illustrated by the compound of formula X or the compound of formula X-A.
• the compound of formula IV or IV-A can be converted to the compound of formula II or II-A by refluxing the compound of formula IV or IV-A with a lower alkanol.
• the particular lower alkanol that is utilized becomes the substituent R 4 in the compound of formula II or II-A.
• the compound of formula II or II-A is reacted with the compound of formula III or III-A to produce a compound of the formula ##STR16## wherein R 3 , R 4 and the dotted bond are as above.
• the methyl substituent at the 4 and 8 positions in the compound of formula XI have an R configuration.
• the place of joinder between the ring and the chain in this compound has an S configuration.
• the above condensation to produce the compound of formula XI or any of the stereoisomers thereof is carried out in an organic solvent medium in the presence of a base and a catalyst which is an organic complex of zero valent palladium.
• a catalyst which is an organic complex of zero valent palladium.
• the preferred catalysts are those complexes of palladium with tri(alkyl or aryl) phosphines.
• the particularly preferred catalysts for use in this reaction are palladium tetrakis(triarylphosphines).
• an organic solvent medium is utilized and the reaction proceeds at temperatures of from -90° C. to +25° C., with temperatures of from about -78° to -20° C. being preferred.
• the reaction is carried out in the presence of a strong base. Any strong base can be utilized, such as the alkali metal lower alkoxides, alkali metal hydrides or lower alkyl alkali metals.
• any conventional inert organic solvent can be utilized as the reaction medium.
• the preferred solvents are organic ethers and those organic solvents which are liquid at the reaction temperature utilized.
• the compound of formula XI is converted to the compound of formula I or its various stereoisomers such as to compounds of formula I-A depending upon the stereoconfiguration of the methyl groups designated by the wavy line in the compound of formula XI Via the following intermediates. ##STR17## wherein R 3 , R 4 and the dotted line are as above.
• the compound of formula XI is converted to the compound of formula XII by treatment with a reducing agent.
• a reducing agent Any conventional reducing agent which reduces oxo groups to hydroxy groups can be utilized in carrying out this procedure.
• the preferred reducing agents are alkali metal borohydride with sodium borohydride being particularly preferred. Any of the conditions conventionally used with these reducing agents can be utilized to carrying out this conversion.
• the compound of formula XII is converted to the compound of XIII by ester hydrolysis. Any of the conditions conventional in ester hydrolysis can be utilized to carry out this conversion.
• the compound of formula XIII is converted to the compound of formula XIV by treating the compound of formula XIII with a diloweralkoxy acetal of a dilower alkyl formamide, in accordance with the standard reaction disclosed by Ruettimann, et al. in Helv. Chim. Acta., 58, 1451 (1975).
• the compound of formula XIV is converted directly to the compound of formula I or its various stereoisomers, such as the compound of formula I-A by hydrogenation utilizing a conventional hydrogenation catalyst, such as platinum or palladium on carbon. Any of the conditions conventional for such hydrogenations can be utilized in this conversion.
• the compound of formula IV or its various stereoisomers such as the compound of formula IV-A can be converted to the compound of formula I or its various steroisomers such as the compound of formula 1-A by first condensing the compound of formula IV or its various stereoisomers such as the compound of formula IV-A with the compound of formula V or its various stereoisomers such as the compound of formula V-A to produce ##STR18## wherein R 3 and the dotted bond are as above and then converting the compound of formula XV to the compound of formula I or I-A via the following intermediates: ##STR19## wherein R 3 and the dotted bond is as above; and R 8 is aryl or lower alkyl.
• the compound of formula IV or its various stereoisomers such as the compound of formula IV-A can be condensed with the compound of formula V or its various stereoisomers such as the compounds of formula V-A to produce the compound of formula XV.
• the compound of formula IV-A is condensed with the compound of formula V-A, the compound of formula XV is produced carrying the methyl substituents represented by the wavy line are in the alpha orientation. This alpha orientation is continued throughout the compounds of formula XVI XVII and XIX to produce the compounds of formula I-A.
• the condensation of the compound of formula IV with the compound of formula V is carried out by refluxing these two reactants in an inert organic solvent.
• an inert organic solvent any conventional inert organic solvent can be utilized.
• those inert organic solvents have a boiling point of 50° C. or greater.
• the preferred inert organic solvents are the high boiling hydrocarbon solvents such as toluene and xylene, etc.
• the compound of formula XV is converted to the compound XVI by treating the compound of formula XV with a catalytically effective amount of a palladium containing catalyst such as those mentioned in connection with the condensation of the compound of formula II with the compound of formula III.
• a palladium containing catalyst such as those mentioned in connection with the condensation of the compound of formula II with the compound of formula III.
• Any conventional organic complex of zero valent palladium can be utilized in carrying out this reaction.
• any conventional inert organic solvent can be utilized.
• the preferred inert organic solvents are dimethylformamide and tetrahydrofuran or diethylether as well as hydrocarbon solvents such as toluene or xylene. This reaction can be carried out at any temperature from 20° C. to the reflux temperature of the reaction mixture.
• the compound of formula XVII is converted to the compound of formula XVIII by reaction with a compound of the formula ##STR20## wherein R 8 is lower alkyl or aryl.
• the compound XVIII is then reacted with the alkali metal cyanoborohydride to produce the compound XIX.
• Both the reaction of the compound of formula XVII with the compound of formula XX to produce the compound of formula XVII and the conversion of the compound of formula XVII to produce the compound of formula XIX are carried out by conventional means in accordance with the Hutchins variation of the Wolff-Kishner reaction. See P. Hutchins., J. Am. Chem. Soc., 1973, 95, 3662.
• Hydrogenation is utilized in converting the compound of formula XIX to the compound of formula I or I-A. This hydrogentation can be carried out utilizing the same procedure described hereinbefore with respect to the conversion of a compound of formula XIV to the compound of formula I or I-A.
• the compound of formula I or its stereoisomers such as the compound of formula I-A is produced by reacting the compound of formula VI or any of its stereoisomers such as the compound of formula VI-A with the compound of formula III or any of its stereoisomers such as the compound of formula III to produce a compound of the formula ##STR21## wherein R 3 , R 6 and the dotted bond are as above. This reaction is carried out in the same manner as described hereinbefore in connection with the condensation reaction of a compound of the formula II with a compound of the formula III to produce a compound of the formula XI.
• the compound of formula XXII is converted to the compound of formula I through its conversion to a compound of formula XIV above.
• the conversion of the compound of formula XXII to the compound of formula XIV above proceeds via the following intermediates: ##STR22## wherein R 3 , R 6 and the dotted line are as above and R 9 is a leaving group.
• the compound of formula XXII is converted to the compound of formula XXIII by treatment with any reducing agent capable of converting an oxo group into a hydroxy group.
• Any conventional reducing agent capable of converting a ketone to a hydroxy group can be utilized in carrying out this reaction.
• the preferred reducing agents are the aluminium hydride reducing agents, such as diisobutylaluminium hydride reducing agents. Any of the conditions conventionally utilized with these reducing agents can be utilized to carry out this conversion.
• the compound of formula XXII is converted to the compound of formula XXIV by converting the hydroxy group into a leaving group.
• the preferred leaving groups are halides, tosyloxy or mesyloxy. Any of the conditions conventional in converting a hydroxy group to a leaving group can be utilized in accordance with this procedure.
• the compound of formula XXIV is converted to the compound of formula XXV by elimination of the leaving group using conventional methods.
• the compound of formula XXI is converted to the compound of formula XIV by reductive cleavage in accordance with the Julia procedure described by J. Bremner, M. Julia, et al.; Tetrahedron Letters, 23, pg. 3265 (1982).
• R 6 is as above.
• This condensation is carried out in an inert organic solvent utilizing a strong base. Any of the bases mentioned hereinbefore can be utilized in carrying out this condensation. Furthermore, in carrying out this reaction, any inert organic solvent can be utilized. Among the preferred inert organic solvents are the ether solvents such as tetrahydrofuran. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, higher or lower temperatures can be utilized.
• Fractions 2-10 (108.2 g) contained (2RS,3E,6R)-6,10-dimethyl-3-undecen-2-yl butyrate corresponding to a weight yield of 81.8%.
• the chemical yield based on GC purities of substrate and products calculates for 107.2 g (88.2%).
• pancreatin grade II, from Porcine Pancreas
• the pH was adjusted to 7.5 by addition 13 mL pf 4N NaOH.
• the reaction was then run at ambient temperature within a pH range of 7.4-7.6 maintained by automatic addition of 4N NaOH.
• the reaction progress was monitored by GC analysis and NaOH consumption.
• a specific activity of 34.5 units/g pancreatin was calculated from the consumption of 1.95 mL of 4N NaOH within the first 16 minutes of the reaction. After 23.5 hours, at a consumption of 36.35 mL of 4N NaOH (22% conversion), an additional 14.1 g of pancreatin was added and the reaction was continued for another 12 hours.
• the hydrolysis was stopped at a consumption of a total of 60.75 mL of 4N NaOH (37% conversion) by addition of 1.0 L of ethanol.
• the mixture was stirred overnight, filtered through a pad of Celite to remove crystallized phosphate salts, and the pad was washed with 2 ⁇ 400 mL of ethanol/water, 1:1 parts by volume.
• To the filtrate was added 500 mL of brine and 900 mL of hexanes/ether 1:1.
• the organic layer was separated and the aqueous layer was extracted with 3 ⁇ 900 mL of hexane/ether (1:1 parts by volume).
• the combined organic extracts were washed with 700 mL of brine, dried over Na 2 SO 4 , filtered and evaporated.
• the hydrolysis was carried out at ambient temperature within a pH range of 6.8-7.2 maintained by automatic addition of 2N NaOH. From the consumption of 0.35 mL of 2N NaOH within the first 18 minutes, the specific activity was calculated to be 0.77 units/mg lipoprotein lipase.
• pancreatin 0.202 mol based on a GC purity of 84.6%) and 4.53 of pancreatin (Grade II, from Porcine pancreas) were added while stirring vigorously.
• the pH was adjusted to 7.5 by addition of 1.3 mL of 2N NaOH and the hydrolysis was carried out at ambient temperature within a pH range of 7.4-7.6 maintained by automatic addition of 2N NaOH. From the consumption of 0.7 mL of 2N NaOH within the first 15 minutes a specific activity of 21 units/g pancreatin was calculated. After 20.5 hours, at a consumption of 24.5 mL (49 mmol) of 2N NaOH (corresponding to 24% conversion), the reaction was quenched with 300 mL of ethanol.
• Example 20 the coupling reactions, in Example 20 were carried out according to the following procedure: An oven-dried 50 mL Schlenk tube equipped with a magnetic stirring bar and capped with a rubber septum was charged under argon with 240-480 mg (5-10 mmol) of 50% NaH dispersion in mineral oil. The mineral oil was removed by 3 cycles of suspending the NaH in a 3-5 mL of hexane, stirring for a short period of time, allowing the solid to settle and removing the supernatant liquid via syringe. After drying the NaH for 5-10 minutes in vacuo, 5-10 mL of dry THF (distilled from sodium/benzophenone ketyl under argon) was injected via syringe.
• THF distilled from sodium/benzophenone ketyl under argon
• the sodium salt of the acetate, i.e. racemic keto ester was reacted with the acetate i.e. (2RS,3E,6R)-6,10-dimethyl-3-undecen-2-yl acetate except that a mixture of 57.5 mg (0.10 mol%) of bis(dibenzylidene acetone)palladium (0) and 40 mg (0.10 mmol, 2 mol%) of 1,2-bis-(diphenylphosphino)ethane in 15 ml of THF was used as the catalyst.
• the coupling product produced was (2RS, 4'RS,8'R)-6-benzyloxy-2-(3'-carbomethoxy-2'-oxo-4',8',12'-trimethyl-5'-tridecenyl-2,5,7,8-tetramethyl chroman. According to TLC analyses the alkylation apparently stopped after ca. 48 hours with some acetate (2RS,6R) remaining unconsumed. Chromatography (200 g silica gel, hexane/ethyl acetate 3% ⁇ 5%) afforded 244 mg (20% recovery) of acetate (2RS,6R) and 2.310 g (78%) of coupling product, i.e.
• keto ester (S)-3-oxo-4-[dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-yl]butanoic acid methyl ester prepared from 2.46 g (6.0 mmol) of the keto ester (92% ee) and 240 mg (5.0 mmol) of 50% NaH dispersion in 25 mL of THF was reacted with a mixture of 1.202 g (5.0 mmol) of the acetate i.e.
• a 3 L, three-necked flask was fitted with a mechanical stirrer and a pH electrode which automatically delivered 4N aqueous NaOH solution from a reservoir.
• the flask was charged with 1170 mL of pH 8 buffer solution (0.05M monobasic potassium phosphate/NaOH), 280.5 g (0.958 mole) of the butyrate which is (2RS,3E,6R)-6,10-Dimethyl-3,9-undecadien-2-yl butyrate, (91.0% chemical purity by GC analysis).
• Stirring was started and the pH of the mixture was adjusted to 7.5 by dropwise addition of sufficient 85% phosphoric acid.
• 7.6 g of Triton X-100 was added, followed by 12.1 g of lipase from a Pseudomonas sp. (Lipase P Amano,).
• the alcohol which is (2R,6R,3E)-6,10-dimethyl-2-hydroxy-3,9-undecadiene contained in fraction 5 was isolated by chromatography on silica gel (543 g of 70-230 mesh) using initially 2% ethyl acetate in hexane as eluent. In this manner 40.8 of the butyrate with a purity of 90.0% was recovered from distillation fraction 5. By eluting with 25% ethyl acetate in hexane, 5.0 g (Kugelrohr distilled) of 100% pure alcohol was recovered from distillation fraction 5.
• the total isolated yields of the alcohol and butyrate were 46.0% and 46.9% respectively, based on GC chemical purity of the various fractions.
• the diastereomeric excess of the alcohol obtained was 95.8%.
• the disatereomeric excess of the butyrate obtained was 93.8%.
• a flame-dried, argon-filled, 5 L three-necked Morton flask was set up with a mechanical stirrer and dry ice/acetone cooling bath.
• the flask was charged with 279.2 g (1.33 mole) of (2R,6R,3E)-6,10-dimethyl-2-hydroxy-3,9-undecadiene having a chemical purity of 93.8% and a diastereomeric excess of ⁇ 95%.
• An addition funnel mounted on the flask was charged via cannula with 860 mL (1.33 mole) of n-butyl lithium (1.55M in hexane solution).
• the reaction mixture was poured in four portions into a separatory funnel containing 1400 mL of saturated NH 4 Cl solution, with shaking between each addition.
• the reaction flask was rinsed into the funnel with 500 mL of water and 600 mL of ether. After thoroughly shaking the mixture, the organic layer was removed and combined with 2 ⁇ 600 mL ether extracts of the aqueous layer.
• the combined organic material was washed with 1 L of water, dried over 550 g of Na 2 SO 4 , filtered and stripped of solvent on the rotovapor, finally under a vacuum less than 1 mm Hg.
• the crude carbonate so obtained weighed 381 g.
• This material was chromatographed in two portions on a total of 8 kg of silica gel using first 2% by volume ethyl acetate in 98% by volume hexane and then 4% by volume ethyl acetate in 96% by volume hexane as the eluent.
• the columns were run at a flow rate of 150-200 mL/minute and 450 mL fractions were collected. The elution of product was monitored by TLC.
• the fractions containing pure carbonate were combined and stripped of solvent under high vacuum to give, altogether, 342.1 g (101% yield) of methyl (2R,6R,3E)-6,10-dimethyl-3,9-undecadien-2-yl carbonate as a colorless liquid.
• a pressure equalizing addition funnel was placed on top and the oxalyl chloride 58.5 mL (0.68 mole, 1.2 equiv.) was added dropwise at about one drop per second. The color became orange, and the temperature increased to about 60° C. as gas evolution began smoothly. The rate of addition was monitored so that gas evolution was not too vigorous. The gas evolved was bubbled through two aqueous sodium hydroxide traps. The slow addition was continued over about 1 hour and then heating was applied with a thermowatch keeping the heat at 60° C.
• the reaction was then poured into a 4000 mL separatory funnel containing 500 mL of crushed ice and 300 mL of 6N HCl. After vigorous shaking the layers were allowed to separate, and after removing the organic layer the aqueous phase was extracted with three portions of 100 mL dichloromethane. The organic phase was washed with 300 mL of saturated aqueous sodium chloride. The aqueous wash was then extracted with the three 100 mL portions of dichloromethane. The combined organics were dried with 100 g Na 2 SO 4 and 30 g MgSO 4 , filtered, and the solvent removed on the rotovap.
• This dark red material was dissolved in 100 mL of 15% ethyl acetate/hexane, and the minimum amount of ethyl acetate required to dissolve all of the material. This solution was then applied to a 500 g plug of silica gel, and five 500 mL hexane fractions were taken followed by five 500 mL fractions with ethyl acetate. Those fractions containing the product were condensed on the rotovap. Those containing only lower Rf materials were discarded. This product amounted to 232 g of yellow oil which was taken up in 1000 mL of hot 5% ethyl acetate/hexane.
• reaction flask did become warm, but no cooling was used.
• 50 mL of anhydrous THF was added by syringe to the Schlenk tube (as a wash) and this wash was also flushed through the cannula. Once pressure was equalized, the bubbler was again opened and positive pressure maintained while the subsequent solutions were prepared.
• the NaH/ketoester solution in the main reaction vessel was now cooled to about -78° C. with a dry ice/acetone bath. While maintaining positive argon pressure, the cannula was disconnected at the ketoester Schlenk tube and connected to the carbonate Schlenk tube. The main vessel bubbler was closed, and by applying a slight vacuum the carbonate solution was transferred to the main reaction flask. 50 mL of anhydrous THF was added (as a wash) to this Schlenk tube by syringe and this wash was passed through the cannula to the reaction flask.
• reaction was diluted with 500 mL of hexane and then quenched with 150 mL of 3N HCl added to 500 mL of crushed ice, all of which was poured into the reaction mixture. Gas was evolved as the acid solution was added. After vigorous mixing in a 4000 mL separatory funnel the layers separated, and the organic layer was washed with 500 mL of saturated aqueous sodium chloride. The aqueous layer was extracted with three 500 mL portions of hexane, then 100 mL of dichloromethane which dissolved the last traces of solids, believed to be organic.
• reaction mixture was analyzed by TLC (25% ethyl acetate/hexane) against starting material. Not being complete, another 9.25 g portion of NaBH 4 was added. After another hour, by TLC, the reaction was still incomplete. Five subsequent portions of NaBH 4 were added. The reaction was then stirred for two days unattended. TLC after that time showed a little starting material still present. The solution was condensed to a volume less than 1,000 mL and a final portion of NaBH 4 was added (8 mole equiv. total).
• 350.6 g (0.59 mole) of this hydroxy ester was dissolved in 1,000 mL of methanol, adding 50 mL ether to get the material into solution. Then 47.5 g (1.19 mole, 2 equiv.) of sodium hydroxide was dissolved in 1,000 mL of methanol, and 18 mL of water. These were mixed in a 5 mL flask equipped with a mechanical stirrer. After stirring at reflux for 3 hours, little reaction had occurred and a second 47.5 g portion of sodium hydroxide was added in 36 mL of water. 500 mL THF (distilled) and 500 mL water were also added and the solution was brought to reflux for 3 hours. The solution was milky white. Refluxing clarified the solution, and as it did, at 1 hour intervals three 100 mL portions of water were added to the solution causing cloudiness to reappear.
• the refractive index detector was marginally useful in deciding where to cut the fractions. Basically, 20 L fractions were taken. After condensing the appropriate fractions on the 5 L rotovap, 140.2 g (45.9% yield) of pure product SYN: [2S,4'R,2(E/Z),5(E),8'R]-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-2,5,11-tridecatrienyl)-6-(phenylmethoxy-2H-1-benzopyran (highest Rf material), was obtained.
• Methyl (S)-[3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-yl]-acetate (25.8 g, 0.070 mole) was dissolved in 50 mL of dry THF contained in a 500 mL three-neck flask equipped with a magnetic stirring bar and argon inlet and outlet adaptors. The flask was swept with argon.
• Methyl phenylsulfone (10.94 g, 0.070 mole) was weighed into a 300 mL Schlenk tube equipped with a stirring bar and septum.
• the Schlenk tube was evacuated, refilled with argon, and charged with 150 mL of dry THF, using a syringe.
• the Schlenk tube and contents were chilled to 0°.
• a 1 L three-neck flask was set up with a stirring bar, argon inlet and exit adapters, and a septum to seal the center neck. This flask was charged with 1.559 g (0.0325 mole) of NaH, 50% in oil. Two 10 mL portions of hexane were used to wash out the oil, a syringe being used to remove the hexane after the solid NaH had settled. The flask was filled with argon and charged with 100 mL of dry THF. The solution in the Schlenk tube was then transferred in via cannula, using 50 mL of dry THF to complete the transfer.
• reaction mixture was allowed to stir overnight, during which time it warmed to room temperature.
• TLC analysis of a 0.2 mL aliquot partitioned between ether and 1N HCl, the reaction was judged to be complete.
• reaction was then quenched by adding 40 mL of 2N HCl and 100 mL of brine, followed by 100 mL of hexane.
• the mixture was transferred to a separatory funnel and shaken.
• the organic layer was separated and the aqueous layer was extracted with 3 ⁇ 25 mL of CH 2 Cl 2 .
• the combined organic layers were dried over MgSO 4 , filtered, and stripped of solvent under reduced pressure.
• the benzyl ether of d- ⁇ -tocopherol (630 mg) was debenzylated by hydrogenation in ethanol/THF (10 mL of a 9:1 parts by volume mixture) over 10% Pd/C (80 mg) at 8° C. for 3 hours under 60 psi of hydrogen.
• the catalyst was filtered and washed and the clear, colorless filtrate was evaporated; all under argon with minimal exposure to air.
• the residue of 510 mg d- ⁇ -tocopherol acquired a pale brownish color on storage.

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